Pyran-4-ylmethyl substituted arylalkylaryl-, arylalkenylylaryl-, and arylalkynylarylurea inhibitors of 5-lipoxygenase

ABSTRACT

Compounds of structure ##STR1## where W is selected from ##STR2## where Q is oxygen or sulfur, R 5  and R 6  are independently selected from hydrogen and alkyl, or R 5  and R 6 , together with the nitrogen atoms to which they are attached, define a radical of formula ##STR3## L 1  and L 2  are independently selected from a valence bond, alkylene, propenylene, and propynylene, R 1 , R 2 , R 3 , and R 4  are independently selected from alkyl, alkoxy, haloalkyl, halogen, cyano, amino, alkoxycarbonyl, and dialkylaminocarbonyl, Y is oxygen, &gt;NR 9  where R 9  is hydrogen or alkyl, or ##STR4## where n=0, 1, or 2, and A is selected from ##STR5## inhibit the biosynthesis of leukotrienes. These compounds are useful in the treatment or amelioration of allergic and inflammatory disease states.

TECHNICAL FIELD

This invention relates to compounds having biological activity toinhibit lipoxygenase enzymes, to pharmaceutical compositions comprisingthese compounds, and to a medical method of treatment. Moreparticularly, this invention concerns certain pyran-4-ylmethylsubstituted arylalkylaryl-, arylalkenylaryl-, and arylalkynylarylureacompounds which inhibit leukotriene biosynthesis, to pharmaceuticalcompositions comprising these compounds and to a method of inhibitinglipoxygenase activity and leukotriene biosynthesis.

BACKGROUND OF THE INVENTION

5-Lipoxygenase is the first dedicated enzyme in the pathway leading tothe biosynthesis of leukotrienes. This important enzyme has a ratherrestricted distribution, being found predominantly in leukocytes andmast cells of most mammals. Normally 5-lipoxygenase is present in thecell in an inactive form; however, when leukocytes respond to externalstimuli, intracellular 5-lipoxygenase can be rapidly activated. Thisenzyme catalyzes the addition of molecular oxygen to fatty acids withcis,cis-1,4-pentadiene structures, converting them to1-hydroperoxytrans,cis-2,4-pentadienes. Arachidonic acid, the5-lipoxygenase substrate which leads to leukotriene products, is foundin very low concentrations in mammalian cells and must first behydrolyzed from membrane phospholipids through the actions ofphospholipases in response to extracellular stimuli. The initial productof 5-lipoxygenase action on arachidonate is 5-HPETE which can be reducedto 5-HETE or converted to LTA₄. This reactive leukotriene intermediateis enzymatically hydrated to LTB₄ or conjugated to the tripeptideglutathione to produce LTC₄. LTA₄ can also be hydrolyzednonenzymatically to form two isomers of LTB₄. Successive proteolyticcleavage steps convert LTC.sub. 4 to LTD₄ and LTE₄. Other productsresulting from further oxygenation steps have also been described in theliterature. Products of the 5-lipoxygenase cascade are extremely potentsubstances which produce a wide variety of biological effects, often inthe nanomolar to picomolar concentration range.

The remarkable potencies and diversity of actions of products of the5-lipoxygenase pathway have led to the suggestion that they playimportant roles in a variety of diseases. Alterations in leukotrienemetabolism have been demonstrated in a number of disease statesincluding asthma, allergic rhinitis, rheumatoid arthritis and gout,psoriasis, adult respiratory distress syndrome, inflammatory boweldisease, endotoxin shock syndrome, atherosclerosis, ischemia inducedmyocardial injury, and central nervous system pathology resulting fromthe formation of leukotrienes following stroke or subarachnoidhemorrhage.

The enzyme 5-lipoxygenase catalyzes the first step leading to thebiosynthesis of all the leukotrienes and therefore inhibition of thisenzyme provides an approach to limit the effects of all the products ofthis pathway. Compounds which inhibit 5-lipoxygenase are thus useful inthe treatment of disease states such as those listed above in which theleukotrienes play an important role.

SUMMARY OF THE INVENTION

In its principal embodiment, the present invention provides certaintriether compounds which inhibit lipoxygenase enzyme activity and areuseful in the treatment of allergic and inflammatory disease states inwhich leukotrienes play a role.

The compounds of this invention and the pharmaceutically acceptablesalts thereof have the structure ##STR6## wherein W is selected from thegroup consisting of ##STR7## wherein Q is oxygen or sulfur, R⁵ and R⁶are independently selected from the group consisting of hydrogen oralkyl of one to four carbon atoms, provided that when L¹ is a valencebond, R⁵ is alkyl of one to four carbon atoms, or R⁵ and R⁶, togetherwith the nitrogen atoms to which they are attached, define a radical offormula ##STR8## R⁷ is selected from the group consisting of hydrogen;alkyl of one to four carbon atoms; haloalkyl of one to four carbonatoms; cyanoalkyl of one to four carbon atoms; phenyl, optionallysubstituted with alkyl of one to four carbon atoms, alkoxy of one tofour carbon atoms, haloalkyl, or halogen; hydroxyalkyl of from one tofour carbon atoms; aminoalkyl of from one to four carbon atoms;carboxyalkyl of from one to four carbon atoms; (alkoxycarbonyl)alkylwhere the alkyl and alkoxy portions each are of one to four carbonatoms; (alkylaminocarbonyl)alkyl, where the alkyl and aminoalkylportions each are of one to four carbon atoms; and Z is --CH₂ --,oxygen, sulfur, or --NR⁸ wherein R⁸ is hydrogen or alkyl of one to fourcarbon atoms.

L¹ is a valence bond or is selected from alkylene of one to three carbonatoms, propenylene, and propynylene.

R¹, R², R³, and R⁴ are independently selected from the group consistingof alkyl of one to four carbon atoms, alkoxy of one to four carbonatoms, haloalkyl, halogen, cyano, amino, alkoxycarbonyl of one to fourcarbon atoms, and dialkylaminocarbonyl where the alkyl portions are eachof one to four carbon atoms.

L² is a valence bond or is selected from alkylene of one to three carbonatoms, propenylene, and propynylene.

Y is selected from the group consisting of oxygen, >NR⁹, where R⁹ ishydrogen or alkyl of one to four carbon atoms, and ##STR9## where n=0,1, or 2.

A is selected from the group consisting of ##STR10## wherein R¹⁰ isalkyl of one to four carbon atoms, ##STR11## wherein R¹¹⁰ is hydrogen oralkyl of one to four carbon atoms.

DETAILED DESCRIPTION OF THE INVENTION Definitions of Terms

As used throughout this specification and the appended claims, the term"alkyl" refers to a monovalent group derived from a straight or branchedchain saturated hydrocarbon by the removal of a single hydrogen atom.Alkyl groups are exemplified by methyl, ethyl, n- and iso-propyl, n-,sec-, iso- and tert-butyl, and the like.

The term "alkylamino" refers to a group having the stucture --NHR'wherein R' is alkyl as previously defined. Example of alkylamino includemethylamino, ethylamino, iso-propylamino, and the like.

The term "alkylaminocarbonyl" refers to an alkylamino group, aspreviously defined, attached to the parent molecular moiety through acarbonyl group. Examples of alkylaminocarbonyl includemethylaminocarbonyl, ethylaminocarbonyl, iso-propylaminocarbonyl, andthe like.

The term "alkanoyl" refers to an alkyl group, as defined above, attachedto the parent molecular moiety through a carbonyl group. Alkanoyl groupsare exemplified by formyl, acetyl, butanoyl, and the like.

The term "propynyl" refers to a straight chain, three-carbon groupcontaining a carbon-carbon triple bond.

The term "hydroxyalkyl" represents an alkyl group, as defined above,substituted by one to three hydroxyl groups with the proviso that nomore than one hydroxy group may be attached to a single carbon atom ofthe alkyl group.

The term "haloalkyl" denotes an alkyl group, as defined above, havingone, two, or three halogen atoms attached thereto and is exemplified bysuch groups as chloromethyl, bromethyl, trifluoromethyl, and the like.

The terms "alkoxy" and "alkoxyl" denote an alkyl group, as definedabove, attached to the parent molecular moiety through an oxygen atom.Representative alkoxy groups include methoxyl, ethoxyl, propoxyl,butoxyl, and the like.

The term "alkoxycarbonyl" represents an ester group; i.e. an alkoxygroup attached to the parent molecular moiety through a carbonyl group.Representative alkoxycarbonyl groups include methoxycarbonyl,ethoxycarbonyl, and the like.

The term "alkenyl" denotes a monovalent group derived from a hydrocarboncontaining at least one carbon-carbon double bond by the removal of asingle hydrogen atom. Alkenyl groups include, for example, ethenyl,propenyl, butenyl, 1-methyl-2-buten-1-yl and the like.

The term "alkylene" denotes a divalent group derived from a straightbranched chain saturated hydrocarbon by the removal of two hydrogenatoms, for example methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene,2,2-dimethylpropylene, and the like.

The term "aminoalkyl" denotes an --NH₂ group attached to the parentmolecular moiety through an alkylene group. Representative aminoalkylgroups include 2-amino-1-ethylene, 3-amino-1-propylene,2-amino-1-propylene, and the like.

The term "carboxyalkyl" denotes a --CO₂ H group attached to the parentmolecular moiety through an alkylene group. Representative carboxyalkylgroups include, 1-carboxyethyl, 2-carboxyethyl, 1-carboxypropyl, and thelike.

The term "(alkoxycarbonyl)alkyl" denotes an alkoxycarbonyl group, asdefined above, attached to the parent molecular moiety through analkylene group. Representative (alkoxycarbonyl)alkyl groups includeethoxycarbonylmethyl, ethoxycarbonylethyl, methoxycarbonylpropyl, andthe like.

The term "(alkylaminocarbonyl)alkyl" denotes an alkylaminocarbonylgroup, as defined above, attached to the parent molecular moiety throughan alkylene group. Examples of (alkylaminocarbonyl)alkyl groups includemethylaminocarbonylmethyl, methylaminocarbonylpropyl,isopropylaminocarbonylmethyl, and the like.

The term "alkenylene" denotes a divalent group derived from a straightor branched chain hydrocarbon containing at least one carbon-carbondouble bond. Examples of alkenylene include --CH═CH--, --CH₂ CH═CH--,--C(CH₃)═CH--, --CH₂ CH═CHCH₂ --, and the like.

In one preferred embodiment, the compounds of this invention have thestructure ##STR12## wherein W, Y, R⁴, and A are as defined above.

Examples of compounds of this embodiment include, but are not limitedto:

4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)-5-fluorophenyl)methoxymethyl]-tetrahydropyran;

4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)phenyl)methoxymethyl]-tetrahydropyran;

4-[3-(4-(N',N'-dimethylaminocarbonyl-N-methylamino)benzyloxy)-5-fluorophenyl)methoxymethyl]tetrahydropyran;

4-[3-(4-(N',N'dimethylaminocarbonyl-N-methylamino)benzyloxy)phenyl)-methoxymethyl]tetrahydropyran;

4-[3-(4-(N',N'-dimethylaminocarbonyl-N-methylamino)benzylthio)phenyl)-methoxymethyl]tetrahydropyran;

4-[3-(4-(N-acetyl-N-methylamino)benzylthio)phenyl)methoxymethyl]-tetrahydropyran;

4-[(3-(4-(N-acetyl-N-methylamino)benzylthio)-5-fluorophenyl)methoxy-methyl]tetrahydropyran;

4-[(3-(4-(N-thioacetyl-N-methylamino)benzylthio)-5-fluorophenyl)methoxy-methyl]tetrahydropyran;

4-[(3-(4-(N',N'-dimethylaminocarbony-N-methylamino)benzyl-N-methylamino)phenyl)oximinomethyl]tetrahydropyran,and

4-[(3-(4-(N-acetyl-N-methylamino)benzyl-N-methylamino)phenyl)-oximinomethyl]tetrahydropyran.

In another preferred embodiment, the compounds of this invention havethe structure ##STR13## wherein W, n, R⁴, and R¹⁰ are as defined above.

Examples of compounds of this embodiment include, but are not limitedto:

E andZ-4-[(3-(4-(N-acetyl-N-methylamino)phenylthio)phenyl)oximinomethyl]tetrahydropyran;

E andZ-O-Methyl-4-[(3-(4-(N-acetyl-N-methylamino)phenylthio)phenyl)-oximinomethyl]tetrahydropyran;

E andZ-O-Methyl-4-[(3-(4-(N-acetyl-N-methylamino)phenylsulfinyl)phenyl)-oximinomethyl]tetrahydropyran;

E- andZ-O-Methyl-4-[(3-(4-(n-acetyl-N-methylamino)phenylsulfonyl)-phenyl)oximinomethyl]tetrahydropyran;

E- and Z-O-Methyl-4-[(3-(4-(N',N'-dimethylaminocarbonyl-N-methylamino)-phenylthio)phenyl)oximinomethyl]

E- and Z-O-Methyl-4-[(3-(4-(N',N'-dimethylaminocarbonyl-N-methylamino)phenylsulfinyl)phenyl)oximinomethyl]tetrahydropyran;and

E- and Z-O-Methyl-4[(3-(4(N',N'-dimethylaminocarbonyl-N-methylamino)phenylsulfonyl)phenyl)oximinomethyl]tetrahydropyran,

In the most preferred embodiment, the compounds of this invention havethe structure ##STR14## wherein W, Y, R⁴, and R¹¹ are as defined above.

Examples of compounds of this embodiment include, but are not limitedto:

E- andZ-O-Methyl-4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)-5-fluorophenyl)oximinomethyl]tetrahydropyran;

E- andZ-4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)5-fluorophenyl)oximinomethyl]tetrahydropyran;

E-andZ-O-Methyl-4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)phenyl)-oximinomethyl]tetrahydropyran;

E- andZ-4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)phenyl)-oximinomethyl]tetrahydropyran;

E- and Z-O-Methyl-4-[(3-(4-(N',N'-dimethylminocarbonyl-N-methylamino)-benzyloxy)phenyl)oximinomethyl]tetrahydropyran;

E- and Z-4-[(3-(4(N',N'-dimethylminocarbonyl-N-methylamino)benzyloxy)-5-fluorophenyl)oximinomethyl]tetrahydropyran;

E- and Z-O-Methyl-4-[(3-(4-(N',N'-dimethylaminocarbonyl-N-methylamino)-benzylamino)phenyl)oximinomethyl]tetrahydropyran;

E- andZ-4-[(3-(4-(N',N'-dimethylaminocarbonyl-N-methylamino)benzyloxy)phen-1-yl)oximinomethyl]tetrahydropyran;

E- and Z-O-Methyl-4-[(3-(4-(N',N'-dimethylaminocarbonyl-N-methylamino)-benzylamino)phenyl)oximinomethyl]tetrahydropyran;

E- andZ-O-Methyl-4-[(3-(4-(N-acetyl-N-methylamino)benzylamino)phenyl)-oximinomethyl]tetrahydropyran;

E- and Z-O-Methyl-4-[(3-(4-(N',N'-dimethylaminocarbonyl-N-methylamino)benzylthio)-5-fluorophenyl)oximinomethyl]tetrahydropyran;

E- and Z-O-Methyl-4-[(3-(4-(N',N'-dimethylaminocarbonyl-N-methylamino)benzylthio)phenyl)oximinomethyl]tetrahydropyran;

E- and Z-4-[(3-(4-(N',N'-dimethylaminocarbonyl-N-methylamino)benxylthio)phenyl)oximiminomethyl]tetrahydropyran;

E- andZ-O-Methyl-4-[(3-(4-(N-acetyl-N-methylamino)benzylthio)phenyl)oximinomethyl]tetrahydropyran;

E- andZ-4-[(3-(4-(N-acetyl-N-methylamino)benzylthio)phenyl)-oximinomethyl]tetrahydropyran;

E- andZ-O-Methyl-4-[(3-(4(N-acetyl-N-methylamino)benxylthio)-5-fluorophenyl)oximinomethyl]tetrahydropyran;

E- andZ-4-[(3-(4-(N-acetyl-N-methylamino)benzylthio)-5-fluorophenyl)oximinomethyl]tetrahydropyran;

E- andZ-O-Methyl-4-[(3-(4-(N-thioacetyl-N-methylamino)benxylthio)-5-fluorophenyl)oximinomethyl]tetrahydropyran;

E- and Z-O-Methyl-4[(3-(4-(N',N'-dimethylaminothiocarbonyl-N-methylamino)benzylthio)phenyl)oximinomethyl]tetrahydropyran;

E- andZ-O-Methyl-4-[(3-(4-N-aminocarbonyul-N-methylamino)benzyloxy]-5-fluorophenyl)oximinomethyl]tetrahydropyran;

E- andZ-O-Methyl-4-[(3-(4-(N'-methylaminocarbonyl-N-methylamino)benzyloxy)-5-fluorophenyl)oximinomethyl]tetrahydropyran;

E- andZ-O-Methyl-4-[(3-(4-N-(piperidin-1-ylcarbonyl)-N-methylamino)benzyloxy)-5-fluorophenyl)oximinomethyl]tetrahydropyran;

E- andZ-O-Methyl-4[(3-(4-(N-(piperidin-1-ylcarbonyl)amino)benzyloxy)-5-fluorophenyl)oximinomethyl]tetrahydropyran;

E- andZ-O-Methyl-4-[(3-(4-((4-morpholinocarbonyl)-N-methylamino)benzyloxy)-5-fluorophenyl)oximinomethyl]tetrahydropyran;

E- andZ-O-Methyl-4-[(3-(4((4-thiomorpholinocarbonyl)-N-methylamino)benzyloxy)-5-fluorophenyl)oximinomethyl]tetrahydropyran;

E- andZ-O-Methyl-4[(3(4-(N-(4-methylpiperazin-1-ylcarbonyl)-N-methylamino)benzyloxy)-5-fluorophenyl)oximinomethyl]tetrahydropyran;

E- andZ-O-Methyl-4-[(3-(4-((N'-(3-bromoprop-1-yl)aminocarbonyl)-N-methylamino)benzyloxy)-5-fluorophenyl)oximinomethyl]tetrahydropyran;

E- andZ-O-Methyl-4-[(3-(4-((N'(3-aminoprop-1-yl)aminocarbonyl)-N-methylamino)benzyloxy)-5-fluorophenyl)oximinomethyl]tetrahydropyran;

E- andZ-O-Methyl-4-[(3-(4-((N'-(3-hyroxyprop-1-yl)aminocarbonyl)-N-methylamino)benzyloxy)-5fluorophenyl)oximinomethyl]tetrahydropyran;

E- andZ-O-Methyl-4-[(3-(4-((N'-(3-ethoxycarbonylprop-1-yl)aminocarbonyl)-N-methylamino)benzyloxy)-5-fluorophenyl)oximinomethyl]tetrahydropyran;

E- andZ-O-Methyl-4-[(3-(4-((N'-(3-carboxyprop-1-yl)aminocarbonyl)-N-methylamino)benzyloxy)-5-fluorophenyl)oximinomethyl]tetrahydropyran;

E- andZ-O-Methyl-4-[(3-(4-((N-(4-hydroxybut-1-yl)aminocarbonyl)-N-methylamino)benzyloxy)-5-fluorophenyl)oximinomethyl]tetrahydropyran;

E- andZ-O-Methyl-4-[(3-(4((N-(4-cyanobut-1-yl)aminocarbonyl)-N-methylamino)benzyloxy)-5-fluorophenyl)oximinomethyl]tetrahydropyran;

E- andZ-O-Methyl-4-[(3-(4-((N-(4-aminobut-1-yl)aminocarbonyl)-N-methylamino)benzyloxy)-5-fluorophenyl)oximinomethyl]tetrahydropyran;

E-andZ-O-Methyl-4-[(3-(4-((N-(3-carboxyprop-1-yl)aminocarbonyl)-N-methylamino)benzyloxy)-5-fluorophenyl)oximinomethyl]tetrahydropyran;

E- andZ-O-Methyl-4-[(3-(4-((N-(3-(N'-methylaminocarbonyl)prop-1-yl)aminocarbonyl)-N-methylamino)benzyloxy)-5-fluorophenyl)oximinomethyl]tetrahydropyran;

E- andZ-O-Methyl-4-[(3-(4-(N',N'-dimethylamincarbonyl-N-methylamino)benzylamino)phenyl)oximinomethyl]tetrahydropyran;and

E- and Z-O-Methyl-4-[(3-(4-(N-acetyl-N-methylamino)benzylamino)phenyl)-oximinomethyl]tetrahydropyran.

Lipoxygenase Inhibition Determination

Inhibition of leukotriene biosynthesis was evaluated in an assay,involving calcium ionophore-induced LTB₄ biosynthesis expressed humanwhole blood. Human heparinized whole blood was preincubated with testcompounds or vehicle for 15 min 37° C. followed by calcium ionophoreA23187 challenge (final concentration of 8.3 μM) and the reactionterminated after 30 min by adding two volumes of methanol containingprostaglandin B₂ as an internal recovery standard. The methanol extractwas analyzed for LTB₄ using a commercially available radioimmunoassay.

The compounds of this invention inhibit leukotriene biosynthesis asillustrated in Table 1.

                  TABLE 1                                                         ______________________________________                                        In Vitro Inhibitory Potencies of Compounds of this Invention                  Against 5-Lipoxygenase from Stimulated LTB.sub.4 Formation in                 Human Whole Blood                                                             Example      IC.sub.50 (10.sup.-6 M)                                          ______________________________________                                        1            100% @ 1.56 μM                                                5            100% @ 0.78 μM                                                43            12% @ 3.13 μM                                                ______________________________________                                    

Pharmaceutical Compositions

The present invention also provides pharmaceutical compositions whichcomprise compounds of the present invention formulated together with oneor more non-toxic pharmaceutically acceptable carriers. Thepharmaceutical compositions may be specially formulated for oraladministration in solid or liquid form, for parenteral injection, or forrectal administration.

The pharmaceutical compositions of this invention can be administered tohumans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, or as an oral or nasal spray.The term "parenteral" administration as used herein refers to modes ofadministration which include intravenous, intramuscular,intraperitoneal, intrasternal, subcutaneous and intraarticular injectionand infusion.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as will as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol, and the like), and suitable mixtures thereof, vegetable oils(such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents, and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents such as sugars, sodium chloride,and the like. Prolonged absorption of the injectable pharmaceutical formmay be brought about by the inclusion of agents which delay absorptionsuch as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides) Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form ifappropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, and tragacanth, and mixturesthereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals that are dispersed inan aqueous medium. Any nontoxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andthe phosphatidyl cholines (lecithins), both natural and synthetic.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers, or propellants which maybe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions, and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated, and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required for toachieve the desired therapeutic effect and to gradually increase thedosage until the desired effect is achieved.

Generally dosage levels of about 1 to about 50, more preferably of about5 to about 20 mg of active compound per kilogram of body weight per dayare administered orally to a mammalian patient. If desired, theeffective daily dose may be divided into multiple doses for purposes ofadministration, e.g. two to four separate doses per day.

Preparation of the Compounds of this Invention

The compounds of this invention can be prepared by a variety ofsynthetic routes. Representative procedures are outlined as follows. Itshould be understood that L¹, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, and W as usedherein correspond to the groups identified above.

A general route to the compounds of this invention is shown in Scheme 1.Alkylation of 1 by treatment with NaH and 2 provides ketone 3.Methoxymethyl derivative 4 is obtained by reduction of 3 with NaBH₄ andalkylation with R⁹ X. Oxime derivative 5 is prepared by reaction of 3with the desired hydroxylamine hydrochloride in the presence of base.##STR15##

The preparation of compounds where R⁶ is alkyl is shown in Scheme2.4-aminobenyzl alcohol is reacted tert-butyldimethylsilyl choloride toform 6, which is then diacylated by treatment sodium acetate and aceticanhydride according to the method of Corley, R. S. and Blout, E. R., J.Am. Chem. Soc. 1947, 69, 755, 761 to form 7. Conversion of 7 to thebromide is accomplished as described by Aizupurua, J. M., Cossio, F. R.,and Paloma, C., J. Org. Chem. 1986, 51, 4941. Arylalkyl-aryl ether 9 isthen prepared from bromide 8 as described in scheme 1. Treatment of 9with one equivalent of LiOH results in removal of one acetyl group toform 10, which is then alkylated by treatment with NaH and the desiredalkyl halide to form 11. The second acyl group is removed by treatmentof 11 with KOH to form key intermediate 12, which can be reacted withtrimethylsilylisocyanate to form 13, or deprotonated with lithiumbis(trimethylsilyl)amide and acylated with the desired carbamyl chlorideto form 14. ##STR16##

The preparation of the compounds of this invention where R⁸ ishaloalkyl, or aminoalkyl is shown in Scheme 3. Amine 12, prepared as inscheme 3, is treated with the desired haloalkylisocyanate to formhaloalkyl derivative 15. Conversion of 15 to azide 16, followed byreduction of the azide with 1,3-propanedithiol provides aminoalkylderivative 17. Compounds in which R⁶ is alkyl are prepared by alkylationof 16 followed by reduction with propanedithiol as described above.##STR17##

The preparation of the compounds of this invention where R⁸ ishydroxyalkyl, carboxyalkyl, (alkoxycarbonyl)alkyl, or(alkylaminocarbonyl)alkyl, is shown in Scheme 4. Amine 12 is treatedwith an alkoxycarbonylalkylisocyanate to provide the alkoxycarbonylalkylderivative 19, which is alkylated by treatment with NaH and R⁶ X.Hydrolysis of ester 20 provides (alkoxycarbonyl)alkyl derivative 21.Reduction of 20 with lithium borohydride or 21 with BH₃ provides thehydroxyalkyl compound 22. Ester 19 is hydrolyzed or reduced as describedabove to prepare the derivatives wherein R⁶ is H. The(alkylaminocarbonyl)alkyl derivatives are prepared from esters 19 and20, or acids 21 and 23 by standard synthetic methods. ##STR18##

The preparation of N-acyl compounds is shown in Scheme 5. Methyl4-(N-methylamino)benzoate (25) is acylated with allyl chloroformate forform 26. Benzyl chloride 27 is prepared by reduction of the ester withlithium triethylborohydride and treatment of the resulting benzylalcohol with PCl₃. Arylalkyl-aryl ether 28 is then prepared fromchloride 27 as described in Scheme 1. Carbamate 28 is hydrolyzedaccording to the method of Corey, E. J., and Suggs, J. W., J. Org.Chem., 1973,38, 3223, and the resulting amine is acylated by treatmentwith lithium hexamethyldisylazide and 4-pentenoyl chloride to form 29.Reaction of 29 with borane-pyridine forms alcohol 30, which is oxidizedto 31 by treatment with Jone's reagent. Amide 32 is prepared by theDCC-catalyzed coupling of 31 and R⁶ R⁷ NH.

Alcohol 30 is converted to primary iodide 33 treatment withmethanesulfonyl chloride and NaI. Displacement of iodide with NaCNproduces alkylcyano derivative 34. Displacement of iodide with NaN₃,followed by reduction of the azide with 1,3-propanedithiol formsalkylamine 35.

The preparation of the arylpropynyl-,arylpropenyl-,and arylpropyl-arylethers is shown in Scheme 6. 4-iodoaniline is converted to urea 36 byacylation with dimethylcarbamyl chloride, followed by alkylation withNaH and MeI. Coupling of 36 with propargyl alcohol provides propynol 37which is converted to chloride 38 by treatment with phosphorustrichloride. The desired arylpropynyl-aryl ether 39 is prepared asdescribed in scheme 1.

Treatment of alkynol 37 with Red-Al (sodium bis(2-methoxyethoxy)aluminum hydride) provides trans allylic alcohol 40, which is thencoupled with 2 in the presence of triphenylphosphine anddiethylaminodicarboxylate. Catalytic hydrogenation of 41 providessaturated compound 42. ##STR19##

The foregoing may be better understood by the following examples, whichare presented for illustration purposes only and are not intended tolimit the scope of the invention.

EXAMPLE 1

Preparation of E- andZ-O-Methyl-4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)-5-fluoro-phenyl)oximinomethyl]tetrahydropyran.

Step 1. Preparation of 4-(N-acetyl-N-methylamino)benzoic acid.

To a solution of N-methyl-4-aminobenzoic acid (2.0 g, 13.2 mmol)dissolved in anhydrous pyridine (13.2 mL) was added acetic anhydride(1.4 mL, 14.5 mmol). The reaction was stirred at ambient temperatureuntil TLC indicated complete reaction (˜22 hours). The resultingsolution was poured into ethyl acetate and the organic phase was washed(3×, 10% HCl; 1×, water; 1×, brine), dried (MgSO₄), filtered, andconcentrated in vacuo to provide the corresponding amide as a colorlesssolid. Recrystallization (ethyl acetate/hexane) afforded pure4-(N-acetyl-N-methylamino)benzoic acid (2.15 g, 84.0%). ¹ H NMR (300MHz, CDCl₃) δ8.18 (2H, br d, J=8.5 Hz), 7.33 (2H, br d, J=8.5 Hz), 3.33(3H, s), 2.0 (3H, br s). MS m/e 194 (M+H)⁺, 211 (M+NH₄)⁺.

Step 2. Preparation of 4-(N-acetyl-N-methylamino)benzyl alcohol.

An oven dried flask, under nitrogen flow, was charged with a stir bar,4-(N-acetyl-N-methylamino)benzoic acid (1.0 g, 5.18 mmol), prepared asin step 1, anhydrous DME (10.3 mL), and anhydrous DMF (3.0 mL). Theresulting solution was cooled to -20° C., and 4-methylmorpholine (0.60mL, 5.4 mmol) and isobutyl chloroformate (0.70 mL, 5.4 mmol) were addedsequentially via syringes. The reaction mixture was stirred under N₂ at-20° C. for 1 h. The resulting yellow mixture was filtered and theprecipitate washed with DME (2×, ˜1 mL). The combined filtrate andwashings were cooled to 0° C. and a solution of sodium borohydride (800mg, 21.1 mmol) in water (2.0 mL) was added dropwise. The reaction wasstirred at 0° C. for 15 min. and quenched with saturated aqueousammonium chloride. The resulting mixture was partitioned between ethylacetate and brine. The combined organic layers were dried (MgSO₄),filtered and concentrated in vacuo to give an oil. Purification by flashchromatography on silica gel (90% ethyl acetate/hexane) provided thecorresponding alcohol as a colorless oil which solidified on standing.Recrystallization from hexane provided 4-(N-acetyl-N-methylamino)benzylalcohol as a colorless solid (543.0 mg, 58.5%). ¹ H NMR (300 MHz, CDCl₃)δ7.45 (2H, d, J=8.5 Hz), 7.18 (2H, d, J=8.5 Hz), 4.75 (2H, s), 3.27 (3H,s), 1.90 (3H, br s). MS m/e 180 (M+H)⁺, 197 (M+NH₄)⁺.

Step 3. Preparation of 4-(N-acetyl-N-methylamino)benzyl bromide.

To a solution of 4-(N-acetyl-N-methylamino)benzyl alcohol (543.0 mg, 3.0mmol), prepared as in step 2, dissolved in dry CH₂ Cl₂ (11.5 mL) wasadded dropwise 1M PBr₃ in CH₂ Cl₂ (3.6 mL, 3.6 mmol) at 0° C. Thereaction was stirred at ambient temperature until TLC indicated completereaction (˜5 hours). The resulting solution was partitioned betweenethyl acetate and brine. The combined organic layers were decolorizedwith charcoal, dried (MgSO₄), filtered through celite and concentratedin vacuo. Purification by flash chromatography on silica gel (40% ethylacetate/hexane) provided 4-(N-acetyl-N-methylamino)benzyl bromide as acolorless solid (595 mg, 81.0%). ¹ H NMR (300 MHz, CDCl₃) δ7.46 (2H, d,J=8.5 Hz), 7.18 (2H, d, J=8.5 Hz), 4.50 (2H, s), 3.27 (3H, s), 1.88 (3H,br s). MS m/e 242 (M+H)⁺, 259/261 (M+NH₄)⁺. Analysis calc'd for C₁₀ H₁₂NOBr: C, 49.61; H, 5.00; N, 5.79. Found: C, 49.35; H, 4.97; N, 5.65.

Step 4. Tetrahydro-4H-pyran-4-(N,O-dimethyl)carboxamide.

A flask was charged with tetrahydro-4H-pyran-4-carboxylic acid (15.3 g,118 mmol), prepared according to the method of J. v. Braun and Z.Kohler, Chem. Ber., 50, 1657 (1917), dichloromethane (295 mL), and astir bar. To the resulting solution was added 1 drop of drydimethylformamide (DMF) and a solution of oxallyl chloride (15.5 mL, 178mmol) in dichloromethane (47 mL). The reaction was stirred at ambienttemperature for one hour and concentrated in vacuo. The resulting slurrywas partially dissolved in dichloromethane (20 mL) and concentrated todryness (2 cycles), then dried briefly under high vacuum. The acidchloride was suspended in dichloromethane (295 mL), cooled to 0° C. anda solution of N,O-dimethylhydroxylamine hydrochloride (12.7 g, 129 mmol)and pyridine (20.9 mL, 259 mmol) in dichloromethane (50 mL) was added.The reaction was quenched by adding excess 10% aqueous hydrochloric acidand stirring for three hours at ambient temperature. After separatingthe layers, the organic layer was washed with saturated aqueous NaHCO₃and brine, dried over MgSO₄, filtered, and concentrated in vacuo toprovide the corresponding amide as an orange liquid (18.9 g, 92%).

Step 5. 3-benzyloxy-5-fluorobromobenzene.

Sodium hydride (80% oil dispersion, 6.0 g, 201 mmol) was added slowly toa solution of benzyl alcohol (16 mL, 155 mmol) in THF (310 mL) at 0° C.DMF (300 mL) was added slowly and the reaction mixture was stirred untilall of the NaH dissolved and gas evolution ceased. A solution of1-bromo-3,5-difluorobenzene (30 g, 155 mmol) in THF (30 mL) was addedand the reaction mixture was stirred for 30 min at ambient temperature.The reaction was quenched with saturated aqueous NH₄ Cl, and thereaction mixture was extracted 3 times with ethyl acetate. The combinedorganic layers were washed with saturated aqueous NH₄ Cl and brine,dried over MgSO₄, filtered, and concentrated in vacuo to give a yellowliquid. 3- 3-benzyloxy-5-fluorobromobenzene (28 g) was isolated bychromatographyy on silica gel (5% ethyl acetate/hexanes).

Step 6. 4-[(3-benzyloxy-5-fluorophenyl)oxomethyl]tetrahydropyran.

An oven-dried flask was charged with 3-benzyloxy-5-flurobromobenzene,prepared as in step 5, freshly dried THF, and a stir bar. The flask wasfitted with a septum, a nitrogen inlet, and a nitrogen outlet beforecooling to -78° C. under a flow of nitrogen. To the cooled reactionmixture was added n-butyl lithium. The resulting solution was stirred at-78° C. for 0.5 hours after which a solution oftetrahydro-4H-pyran-4-(N,O-dimethyl)carboxamide (1.7 g, 10.62 mmol),prepared as in step 4, in THF was added. The reaction mixture wasstirred 0.5 hours at -78° C., 0.5 hours at ambient temperature, and thenquenched with water. The reaction mixture was partitioned between waterand ethyl acetate. The organic layer was washed with saturated aqueousNH₄ Cl and brine, dried over MgSO₄, filtered and concentrated in vacuo.Pure 4-[(3-benzyloxy-5-fluorophenyl)oxomethyl] tetrahydropyran wasobtained by chromatography on silica gel.

Step 7. 4-[(3-hydroxy-5-fluorophenyl)oxomethyl]tetrahydropyran.

To a suspension of palladium on carbon (1.5 g) in ethanol (30 mL) underN₂ was added a solution of4-[(3-benzyloxy-5-flourophenyl)oxomethyl]-tetrahydropyran (3.7 g, 12mmol), prepared as in step 6, in ethanol (70 mL). The reaction mixturewas flushed three times with hydrogen, was then stirred for three hoursunder positive hydrogen pressure. The reaction mixture was flushed withN₂, filtered through a pad of celite, and concentrated in vacuo to yield4-[(3-hydroxy-5-fluorophenyl)oxomethyl]tetrahydropyran (2.17 g, 81%) asa white powder which was used without further purification.

Step 8.4-[(3-(4-N-acetyl-N-methylamino)benxyloxy)-5-fluoro-phenyl)oxomethyl]tetrahydropyran.

To a solution of 4-[(3-hydroxy-5-fluorophenyl)oxomethyl]tetrahydropyran(300 mg, 1.34 mmol), prepared as in step 7, in DMF (2.6 mL) was addedNaH (60% oil dispersion, 107 mg, 2.68 mmol). The reaction mixture wasstirred for one hour at ambient temperature, and then a solution of4-(N-acetyl-N-methylamino) 4-(N-acetyl-N-methylamino)benzyl bromide (246mg, 1.02 mmol) in DMF was added. The reaction mixture was stirred for 18hours at ambient temperature and then was poured into an ethyl acetate,saturated aqueous NH₄ Cl mixture. The layers were separated, and theorganic phase was washed once with saturated aqueous NH₄ Cl, twice withbrine, dried over MgSO₄, filtered, and concentrated in vacuo.Chromatography of silica gel (50% ethyl acetate/hexanes, then ethylacetate) provided4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy-5-fluoro-phenyl)oxomethyl]tetrahydropyranas a yellow oil (248 mg, 63%).

Step 9. E- andZ-O-Methyl-4[(3-(4-(N-acetyl-N-methylamino)benzyloxy)-5-fluoro-phenyl)oximinomethyl]tetrahydropyran.

A solution of4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)-5-fluorophenyl)oxomethyl]tetrahydropyran(220 mg, 0.60 mmol), prepared as in step 8, O-methylhydroxylaminehydrochloride (501 mg, 6.00 mmol), and sodium acetate (816 mg, 6.00mmol) was stirred at 40°-50° C. for 24 hours. AdditionalO-methlhydroxylamine hydrochloride (6.00 mmol), and sodium acetate (6.00mmol) were added and the reaction mixture was stirred for 72 hours at50° C. and 4 hours at reflux. The reaction mixture was cooled to ambienttemperature and was poured into an ethyl acetate, saturated aqueous NH₄Cl mixture. The layers were separated, and the organic phase was washedonce with saturated aqueous NH₄ Cl, twice with brine, dried over MgSO₄,filtered, and concentrated in vacuo. Chromatography on silica gel (70%ethyl acetate/hexanes, then ethyl acetate) providedO-Methyl-4-[(3-4-(N-acetyl-N-methylamino)benzyloxy)-5-fluoro-phenyl)oximinomethyl]tetrahydropyran(92% mg, 39%) as a mixture of the E and Z oxime isomers. ¹ H NMR (300MHz, CDCl₃) δ7.47 (2H, br d, J=8.5 Hz), 7.22 (2H, br d, J=8.5 Hz),6.82-6.53 (3H, m, 5.08 and 5.05 (2H, 2s), 3.98 (2H, dt, J=12,3,3 Hz),3.95 and 3.82 (3H, 2s), 3.34-3.52 (2.5H, m), 3.28 (3H, br s), 2.64(0.5H, pentet, J=7.5 Hz), 1.90 (3H, br s), 1.54-1.72 (4H, m). MS m/e 415(M+H)⁺, 432 (M+NH₄)⁺. Analysis calc'd for C₂₃ H₂₇ FN₂ O₄ : C, 66.65; H,6.57; N, 6.76. Found: C, 66.94; H, 6.70; N, 6.49.

EXAMPLE 2

Preparation of E- andZ-4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)-5-fluoro-phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 1,step 9, except substituting hydroxylamine hydrochloride forO-methylhydroxylamine hydrochloride.

EXAMPLE 3

Preparation of E- andZ-O-Methyl-4-[(3-(4-N-acetyl-N-methylamino)benzyloxy)phenyl)oximinomethyl]tetrahydropyran.

Step 1. 3-(methyloxymethoxy)bromobenzene.

To a solution of 3-bromophenol (27.4 g, 158 mmol) in CH₂ Cl₂ was addedchloromethyl methyl ether (18 mL, 237 mmol). The reaction mixture wascooled to 0° C. and diisopropylethylamine (55 mL, 316 mmol) was addedand the cold bath was removed. The reaction mixture was stirred for 3hours at ambient temperature and then poured into 10% aqueous HCl. Thelayers were separated and the aqueous phase was extracted 4 times withCH₂ Cl₂. The combined organic layers were washed once each withsaturated aqueous NaHCO₃, 15% aqueous NaOH, and brine, dried over MGSO₄,filtered, and concentrated in vacuo to provide3-methyloxymethoxybromobenzene as a yellow oil.

Step 2. 4-[(3-methyloxymethoxyphenyl)oxomethyl]tetrahydropyran.

An oven-dried flask was charged with 3-methoxymethoxy)bromobenzene (2.29g, 10.62 mmol), prepared as in step 1, freshly dried THF (43 mL), and astir bar. The flask was fitted with a septum, a nitrogen inlet, and anitrogen outlet before cooling to -78° C. under a flow of nitrogen. Tothe cooled reaction mixture was added n-butyl lithium (4.24 mL, 2.5M,10.62 mmol in hexanes). The resulting solution was stirred at -78° C.for 0.5 hours after which a solution oftetrahydro-4H-pyran-4-(N,O-dimethyl)carboxamide (1.7 g, 10.62 mmol),prepared as in Example 1, step 4, in THF (10 mL) was added. The reactionmixture was stirred 0.5 hours at -78° C., 0.5 hours at ambienttemperature, and then quenched with water. The reaction mixture waspartitioned between water and ethyl acetate. The organic layer waswashed with saturated ammonium chloride and brine, dried over MgSO₄,filtered and concentrated in vacuo to provide a yellow oil. Pure4-[(3-methoxmethoxyphenyl)oxomethyl]tetrahydropyran (1.5 g, 57%) wasobtained by chromatography on silica gel (30% ethyl acetate/hexanes).

Step 3. 4-[(3-hydroxyphenyl)oxomethyl]tetrahydropyran.

The methyloxymethoxy group was removed by treatment of4-[(3-methyloxymethoxyphenyl)oxomethyl]tetrahydropyran (0.82 g, 3.27mmol), prepared as in step 2 with concentrated hydrochloric acid (2.45mL, 0.75 mL/mmol) in THF (13 mL) at ambient temperature for 0.5 hours.The reaction mixture was partitioned between water and ethyl acetate andthe aqueous layer was extracted twice with ethyl acetate. The combinedorganic layers were washed with saturated aqueous sodium bicarbonate andbrine, dried over MgSO₄, filtered, and concentrated in vacuo to provide4-[(3-hydroxyphenyl)oxomethyl]tetrahydropyran as a brown solid (0.65 g,96%) which was used without further purification.

Step 4. E- andZ-O-Methyl-4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 1,steps 8 and 9, except substituting4-[(3-hydroxyphenyl)oxomethyl]tetrahydropyran for4-[(3-hydroxy-5-fluorophenyl)oxomethyl]tetrahydropyran

EXAMPLE 4

Preparation of E- andZ-4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 2,except substituting 4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)phenyl)oxomethyl]tetrahydropyran, prepared as in Example 3,for4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 5

Preparation of E- andZ-O-Methyl-4-[(3-(4-N',N'-dimethylaminocarbonyl-N-methylamino)benzyloxy)-5-fluoro-phenyl)oximinomethyl]tetrahydropyran.Step 1. Preparation of methyl 4-(N-methylaminocarbonyl)aminobenzoate.

A solution of methyl 4-aminobenzoate (15 g, 99 mmol), and methylisocyanate (11.8 mL, 200 mmol) in toluene (400 mL) was heated at 100° C.under N₂ for 3 hours during which time a precipitate formed slowly.Additional methyl isocyanate (11.8 mL, 200 mmol) was added and heatingwas continued for 2 hours. The reaction mixture was cooled to 0° C. andfiltered. The precipitate was washed with ether and vacuum-dried to givemethyl 4-(N-methylaminocarbonyl)aminobenzoate as a colorless solid (17.5g, 85%).

Step 2. Preparation of methyl4(N',N'-dimethylaminocarbonyl-N-methylamino)benzoate.

To a 0° C. suspension of NaH (80% oil dispersion, 3.60 g, 120 mmol) inTHF (200 mL) under N₂ was added a solution of methyl4-(N-methylaminocarbonyl)aminobenzoate (10.0 g, 48 mmol), prepared as instep 1, in THF (40 mL). The reaction mixture was stirred at 0° C. untilgas evolution ceased, then the cold bath was removed and stirring wascontinued for 1.5 hours. A solution of iodomethane (6.6 mL, 106 mmol) inDMF (24 mL) was added and the reaction mixture was stirred for 72 hoursat ambient temperature. NaH (2.0 g), and iodomethane (5.0 mL) were thenadded and the reaction mixture was stirred for an additional 2 hours.The reaction mixture was poured slowly into ice-water and the organicswere stripped off in vacuo. The aqueous solution was extracted withethyl acetate (10x). The combined organic layers were dried over MgSO₄,filtered, and concentrated. Pure methyl4-(N',N'-dimethylaminocarbonyl-N-methylamino)benzoate (6.62 g, 58%) wasobtained as a colorless oil which crystallized on standing afterchromatography on silica gel (40%, then 50% ethyl acetate/hexanes). mp71°-73° C.

Step 3. Preparation of 4N',N'-dimethylaminocarbonyl-N-methylamino)benzylalcohol.

To a 0° C. solution of methyl 4(N',4(N',N'-dimethylaminocarbonyl-N-methylamino)benzoate (1.50 g, 6.35mmol), prepared as in step 2 in THF (11.4 mL) was added lithiumtriethylborohydride (1.0M solution in THF, 14 mmol). The reactionmixture was stirred for 1 hour. Water (3.0 mL) and H₂ O₂ (30% aqueoussolution, 5.0 mL) were added cautiously and the reaction mixture wasstirred at 45° C. for 20 min. Aqueous HCL (6M, 8.0 mL) was added and thereaction mixture was stirred at reflux for 14 hours. The reactionmixture was cooled to ambient temperature and poured into ethyl acetate.The aqueous phase was extracted three times with ethyl acetate. Thecombined organic layers were dried over MgSO₄, filtered, andconcentrated in vacuo.4-(N',N'-dimethylaminocarbonyl-N-methylamino)benzyl alcohol (797 mg,61%) was isolated as a colorless solid by chromatography on silica gel(ethyl acetate). mp 65°-66° C.

Step 4. Preparation of4-(N',N'-dimethylaminocarbonyl-N-methylamino)benzyl chloride.

To a stirred solution at -23° C. under N₂ of4-(N',N'-dimethylaminocarbonyl-N-methylamino)benzyl alcohol (77.0 mg,0.37 mmol), prepared as in step 4, in dry CH₂ Cl₂ (3.7 mL) was addedtriethylamine (67.0 μL, 0.48 mmol), and methanesulfonyl chloride (34.0μL, 0.44 mmol). The reaction mixture was stirred at ambient temperatureuntil TLC indicated complete reaction (˜5 hours). The resultant solutionwas poured into ethyl acetate and the organic phase was washed (2 X,water; 2×, brine), dried (MgSO₄), filtered and concentrated in vacuo.Purification by flash chromatography on silica gel (70% ethylacetate/hexane) provided4-(N',N'-dimethylaminocarbonyl-N-methylamino)benzyl chloride (56.0mg,67.0%) as a colorless oil which crystallized on standing at -25° C.mp 38.5°-39° C. ¹ H NMR (300 MHz, CDCl₃) δ7.34 (2H, d, J=8.5 Hz), 7.04(2H, d, J=8.5 Hz), 4.57 (2H, s), 3.22 (3H, s), 2.71 (6H, s). MS m/e 227(M+H⁺, 244 (M+NH₄)⁺.

Step 5, E- andZ-O-Methyl-4-[(3-(4-(N',N'-dimethylaminocarbonyl-N-methylamino)benzyloxy)-5-fluorophenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared as a 1:1 mixture of E:Z isomersaccording to the method of Example 1, steps 8 and 9, except substituting4-(N',N'-dimethylaminocarbonyl-N-methylamino)benzyl chloride, preparedas in step 4, for 4-(N-acetyl-N-methylamino)benzyl bromide. ¹ H NMR (300MHz, CDCl₃) δ7.38 (2H, d, J=8 Hz), 7.07 (2H, d, J=8 Hz), 6.53-6.80 (3H,m), 5.01 and 4.98 (2H, 2s), 3.98 (2H, br m), 3.93 and 3.82 (3H, 2s),2.72 (6H, s), 2.60-2.72 (0.5H, m), 1.89 (1H, dq, J=4.5, 13.5, 13.5, 13.5Hz), 1.54-1.71 (3H, m). MS m/e 444 (M+H)⁺, 461 (M+NH₄)⁺. Analysis calc'dfor C₂₄ H₃₀ FN₃ O₄ : C, 64.99; H, 6.82; N, 9.47. Found: C, 65.08; H,6.70; N, 9.31.

EXAMPLE 6

Preparation of E- andZ-4-[(3-(4-(N',N'-dimethylaminocarbonyl-N-methylamino)-benzyloxy)-5-fluoro-phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 2,except substituting4[(3-(4-(N',N'-dimethylaminocarbonyl-N-methylamino)benzyloxy)-5-fluoro-phenyl)oximinomethyl]tetrahydropyran,prepared as in Example 5, for4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)-5-fluoro-phenyl)oxomethyl]tetrahydropyran.

EXAMPLE 7

Preparation of E- andZ-O-Methyl-4[(3-(4-(N',N'-dimethylaminocarbonyl-N-methylamino)benzyloxy)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 5,except substituting 4-[(3-hydroxyphen-1-yl)oxomethyl]tetrahydropyran,prepared as in Example 3, for4-[(3-hydroxy-5-fluorophen-1-yl)oxomethyl]tetrahydropyran.

EXAMPLE 8

Preparation of E- andZ-4-[(3-(4-(N',N'-dimethylaminocarbonyl-N-methylamino)-benzyloxy)phen-1-yl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 2,except substituting4-[(3-(4-(N',N'-dimethylaminocarbonyl-N-methylamino)benzyloxy)phenyl)oxomethyl]tetrahydropyran,prepared as in Example 7, for4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)-5-fluoro-phenyl)oxomethyl]tetrahydropyran.

EXAMPLE 9

Preparation of E- andZ-O-Methyl-4-[(3-(4-(N',N'-dimethylaminocarbonyl-N-methylamino)benzylamino)phenyl)oximinomethyl]tetrahydropyran.

Step 1. Preparation of N-t-Boc-3-bromoaniline.

3-bromoaniline (10 g, 58.1 mmol) and di-tert-butyldicarbonate (19.0 g,87.1 mmol) were dissolved in 2M aqueous sodium hydroxide and heated atreflux for 1 hour. After cooling to ambient temperature, the reactionmixture was extracted with ethyl acetate. The organic layer was washed(saturated aqueous ammonium chloride, 1x; water, 1x; and brine, 2x),dried (MgSO₄), filtered, concentrated in vacuo, and dried under highvacuum to provide N-t-Boc-3 bromoaniline as a colorless solid (15.8 g,100%). mp 83° C. ¹ H NMR (300 MHz, CDCl₃) δ7.66 (1H,br m), 7.08-7.23(3H, m), 6.46 (1H, br s), 1.52 (9H, s). MS m/e 272/274 (M+H)⁺, 289/291(M+NH₄)⁺.

Step 2. Preparation of4-[(3-t-butyloxycarbonylaminophenyl)oxomethyl]-tetrahydropyran.

The desired compound is prepared according to the method of Example 1,step 6, except substituting N-t-Boc-3 bromoaniline. prepared as in step1, for 3-benzyloxy-5-fluorobromobenzene.

Step 3. Preparation of 4-[(3-aminophenyl)oxomethyl]tetrahydropyran.

The desired compound is prepared by reaction of a solution in CH₂ Cl₂ of4-[(3-t-butyloxycarbonylaminophenyl)oxomethyl]tetrahydropyran, preparedas in step 2, with trifluoroacetic acid.

Step 4. Preparation of E andZ-O-Methyl-4-[(3-(4-(N',N'-dimethylaminocarbonyl-N-methylamino)benzylamino)phenyl)oxomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 5,step 5, except substituting 4-(3-aminophenyl)-4-methoxytetrahydropyran,prepared as in step 3, for4-[(3-hydroxy-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 10

Preparation of E- andZ-O-Methyl-4-[(3-(4-N-acetyl-N-methylamino)benzylamino)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 9,except substituting 4-(N-acetyl-N-methylamino)benzyl bromide, preparedas in Example 1, step 3, for4-(N',N'-dimethylaminocarbonyl-N-methylamino)benzyl chloride.

EXAMPLE 11

Preparation of E andZ-O-Methyl-4-[(3-(4-(N-acetyl-N-methylamino)phenylthio)phenyl)-oximinomethyl]tetrahydropyran.

Step 1. Preparation of N-t-Boc-4-bromoaniline.

The desired compound is prepared according to the method of Example 9,step 1, except substituting 4-iodoaniline for 3-bromoaniline.

Step 2. Preparation of3-(4-(t-butyloxycarbonylamino)phenylthio)bromobenzene.

The desired material is prepared by reaction of N-t-Boc-4-iodoaniline,prepared as in step 1, and 3-bromothiophenol in the presence ofcopper(I) iodide.

Step 3. Preparation of 3-(4-aminophenylthio)bromobenzene.

The desired material is prepared according to the method of Example 9,step 3, except substituting3-(4-(t-butyloxycarbonylamino)phenylthio)bromobenzene, prepared as instep 2, for4-[(3-t-butyloxycarbonylaminophenyl)oxomethyl]tetrahydropyran.

Step 4. Preparation of 3-(4-(N-acetylamino)phenylthio)bromobenzene.

The desired compound is prepared according to the method of Example 1,step 1, except substituting 3-(4-aminophenylthio)bromobenzene preparedas in step 3, for N-methyl-4-aminobenzoic acid.

Step 5. Preparation of3-(4-(N-acetyl-N-methylamino)phenylthio)bromobenzene.

The desired compound is prepared according to the method of Example 5,step 3, except substituting 3-(4-(N-acetylamino)phenylthio)bromobenzene,prepared as in step 4, for 4-(N-methylaminocarbonyl)aminobenzoate.

Step 6. Preparation of4[(3-(4-(N-acetyl-N-methylamino)phenylthio)phenyl)oxomethyl]-tetrahydropyran.

The desired compound is prepared according to the method of Example 1,step 6 except substituting3-(4-(N-acetyl-N-methylamino)phenylthio)bromobenzene, prepared as instep 5, for 3-benzyloxy-5-fluorobromobenzene.

Step 7. Preparation of E andZ-O-Methyl-4-[(3-(4-(N-acetyl-N-methylamino)phenylthio)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 1,step 9, except substituting4-[(3-(4-(N-acetyl-N-methylamino)phenylthio)phenyl)oxomethyl]-tetrahydropyran,prepared as in step 6, for4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)-5-fluorophen-1-yl)oxomethyl]tetrahydropyran.

EXAMPLE 12

Preparation of Preparation of E andZ-4-[(3-(4-(N-acetyl-N-methylamino)phenylthio)-phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 2,except substituting4-[(3-(4-(N-acetyl-N-methylamino)phenylthio)phenyl)oxomethyl]tetrahydropyran,prepared as in Example 11, step 6, for4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)-5-fluorophen-1-yl)oxomethyl]tetrahydropyran.

EXAMPLE 13

Preparation of E- and Z-O-Methyl-4-8(3-(4-(N',N'-dimethylaminocarbonyl-N-methylamino)benzylthio)phenyl)oximinomethyl]tetrahydropyran.Step 1. Preparation of 4-[(3-thiophenyl)oxomethyl]tetrahydropyran.

The desired material is prepared according to the method of Example 3,step 2, except substituting 3-bromothiophenol for3-(methoxymethoxy)bromobenzene, and using 2.2 equiv. of n-BuLi.

Step 2. Preparation of E- andZ-O-Methyl-4-[(3-(4-(N',N'-dimethylaminocarbonyl-N-methylamino)benzylthio)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 5,except substituting 4-[(3-thiophenyl)oxomethyl]tetrahydropyran, preparedas in step 1, for4-[(3-hydroxy-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 14

Preparation of E- andZ-4-[(3-(4-(N',N'-dimethylaminocarbonyl-N-methylamino)benzylthio)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 2,except substituting4-[(3-(4-(N',N'-dimethylaminocarbonyl-N-methylamino)-benzylthio)phenyl)oxomethyl]tetrahydropyran,prepared as in Example 13, for4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)-5-fluorophen-1-yl)oxomethyl]tetrahydropyran.

EXAMPLE 15

Preparation of E- andZ-O-Methyl-4-[(3-(4-(N-acetyl-N-methylamino)benzylthio)-phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 1,steps 8 and 9, except substituting4-[(3-thiophenyl)oxomethyl]tetrahydropyran, prepared as in Example 13,step 1, for 4-[(3-hydroxy-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 16

Preparation of E- andZ-4-[(3-(4-(N-acetyl-N-methylamino)benzylthio)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 2,except substituting4-[(3-(4-(N-acetyl-N-methylamino)-benzylthio)phenyl)oxomethyl]tetrahydropyran,prepared as in Example 15, for4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)-5-fluorophen-1-yl)oxomethyl]tetrahydropyran.

EXAMPLE 17

Preparation of E- andZ-O-Methyl-4-[(3-(4-(N-acetyl-N-methylamino)benzylthio)-5-fluorophenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 1,except substituting α-toluenethiol for benzyl alcohol.

EXAMPLE 18

Preparation of E- andZ-4-[(3-(4-(N-acetyl-N-mehtylamino)benzylthio)-5-fluorophenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 2,except substituting4-[(3-(4-(N-acetyl-N-mehtylamino)benzylthio-5-fluorophenyl)oxomethyl]tetrahydropyran,prepared as in Example 17, for4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)-5-fluorophen-1-yl)oxomethyl]tetrahydropyran.

EXAMPLE 19

Preparation of E- andZ-O-Methyl-4[(3-(4-N-thioacetyl-N-methylamino)benzylthio)-5-fluorophenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared by treatment of E- and Z-O-methyl-4-[(3-(4-(N-acetyl-N-methylamino)benzylthio)-5-fluorophenyl)oxomethyl]tetrahydropyran,prepared as in Example 17, with Lawesson's Reagent ([2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) accordingto the method of Katah, A., Kashima, C., and Omote, Y. Heterocycles,1982, 19(12), 2283.

EXAMPLE 20

Preparation of E- andZ-O-Methyl-4-[(3-(4-(N',N'-dimethylaminothiocarbonyl-N-methylamino)benzylthio)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 19,except substituting E- andZ-O-methyl-4-[(3-(4-(N',N'-dimethylaminothiocarbonyl-N-methylamino)benzyloxy)-5-fluorophen-1-yl)oxomethyl]tetrahydropyran,prepared as in Example 13, for E- andZ-O-Methyl-4-[(3-(4-(N-acetyl-N-methylamino)benzylthio)-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 21

Preparation of E andZ-O-Methyl-4-[(3(4-N-acetyl-N-methylamino)phenylsulfinyl)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared by treatment of E andZ-O-Methyl-4-[(3-(4-(N-acetyl-N-methylamino)phenylthio)phenyl)oximinomethyl]tetrahydropyran,prepared as in Example 11, with sodium metaperiodate as described in EPA409 413.

EXAMPLE 22

Preparation of E andZ-O-Methyl-4-[(3-(4-(N-acetyl-N-methylamino)phenylsulfonyl)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared by treatment of E andZ-O-Methyl-4-[(3-(4-(N-acetyl-N-methylamino)phenylthio)phenyl)oximinomethyl]tetrahydropyran,prepared as in Example 11, with potassium peroxymonosulphate asdescribed in EPA 409 413.

EXAMPLE 23

Preparation of E- andZ-O-Methyl-4-[(3-(4-((N',N'-dimethylaminocarbonyl)aminomethyl)benzyloxy)-5-fluorophenyl)oximinomethyl]tetrahydropyran.

Step 1. Preparation of4-[(3-(4-bromomethylbenzyloxy)-5-fluorophenyl)oxomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 1,step 8, except substituing α,α'-dibromo-p-xylene for4-(N-acetyl-N-methylamino)benzyl bromide.

Step 2. Preparation of4-[(3-(4-N',N'-dimethylaminocarbonyl)aminomethyl)benzoyloxy)-5-fluorophenyl)oxomethyl]tetrahydropyran.

The desired material is prepared by reaction of a solution of1,1-dimethylurea in DMF with NaH and4-[(3-(4-bromomethylbenzyloxy)-5-fluorophenyl)oxomethyl]tetrahydropyranwhich is prepared as described in step 1.

Step 3. Preparation of E- andZ-O-Methyl-4-[(3-(4-((N',N'-dimethylaminocarbonyl)aminomethyl)benzyloxy)-5-fluorophenyl)oximinomethyl]-tetrahydropyran.

The desired compound is prepared according to the method of Example 1,step 9, except substituting4-[(3-(4-((N',N'-dimethylaminocarbonyl)aminomethyl)benzyloxy)phenyl)oxomethyl]tetrahydropyran,prepared as in step 2, for4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)-5-fluorophenyl)oxomethyl]tetrahydropyran.EXAMPLE 24

Preparation of E andZ-O-Methyl-4-[(3-(4-(N-acetyl)aminomethyl)benzyloxy)-5-fluorophenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 23,except substituting acetamide for 1,1- dimethylurea.

EXAMPLE 25

Preparation of E- andZ-O-Methyl-4-[(3-(4-(((N',N'-dimethylaminocarbonyl-N-methylamino)methyl)benzyloxy)-5-fluorophenyl)oximinomethyl]tetrahydropyran.

Step 1. Preparation of4-[(3-(4-((N',N'-dimethylaminocarbonyl-N-methylamino)methyl)benzyloxy)-5-fluorophenyl)oxomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 5,step 2, except substituting4-[(3-(4-((N',N'-dimethylaminocarbonyl)aminomethyl)benzyloxy)-5-fluorophenyl)oxomethyl]tetrahydropyran,prepared as in Example 23, for methyl4-(N-methylaminocarbonyl)aminobenzoate.

Step 2. Preparation of E- andZ-O-methyl-4[(3-(4-(((N',N'-dimethylaminocarbonyl)-N-methylamino)methyl)benzyloxy)-5-fluorophenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 1,step 9, except substituting4-[(3-(4-(((N',N'-dimethylaminocarbonyl)-N-methylamino)methyl)-benzyloxy)phenyl)oxomethyl]tetrahydropyran,prepared as in step 2, for4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 26

Preparation of E andZ-O-Methyl-4-[(3-(4-(N-acetyl-N-methyl)aminomethyl)benzyloxy)-5-fluorophenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 25,except substituting4-[(3-(4-(N-acetyl)aminomethyl)benzyloxy)-5-fluorophenyl)oxomethyl]tetrahydropyran,prepared as in Example 24, for4-[(3-(4-((N',N'-dimethylaminocarbonyl)aminomethyl)benzyloxy)-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 27

Preparation of E- andZ-O-Methyl-4-[(3-(4-((N',N'-dimethylaminocarbonyl)aminomethyl)benzyloxy)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 23,except substituting 4-[(3-hydroxyphenyl)oxomethyl]tetrahydropyran,prepared as in Example 3, step 3, for4-[3-hydroxy-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 28

Preparation of E andZ-O-Methyl-4-[(3-(4-(N-acetyl)aminomethyl)benzyloxy)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 24,except substituting 4-[(3-hydroxyphenyl)oxomethyl]tetrahydropyran,prepared as in Example 3, step 3, for4-[(3-hydroxy-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 29

Preparation of E- andZ-O-Methyl-4-[(3-(4-(((N',N'-dimethylaminocarbonyl)-N-methylamino)methyl)benzyloxy)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 25,except substituting 4-[(3-hydroxyphenyl)oxomethyl]tetrahydropyran,prepared as in Example 3, step 3, for4-[(3-hydroxy-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 30

Preparation of E andZ-O-Methyl-4-[(3-(4-(N-acetyl-N-methyl)aminomethyl)benzyloxy)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 26,except substituting 4-[(3-hydroxyphenyl)oxomethyl]tetrahydropyran,prepared as in Example 3, step 3, for4-[(3-hydroxy-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 31

Preparation of E- andZ-O-Methyl-4-[(3-((N',N'-dimethylaminocarbonyl)aminomethyl)benzylthio)-5-fluorophenyl)oximinomethyl]-tetrahydropyran.

The desired compound is prepared according to the method of Example 23,except substituting4-[93-thioxy-5-fluorophenyl)oxomethyl]tetrahydropyran, prepared as inExample 17, for 4-[(3-hydroxy-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 32

Preparation of E- andZ-O-Methyl-4-[(3-(4-((N',N'-dimethylaminocarbonyl)aminomethyl)benzylthio)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 23,except substituting 4-[(3-thiophenyl)oxomethyl]tetrahydropyran, preparedas in Example 13, step 1, for4-[(3-hydroxy-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 33

Preparation of E- andZ-O-Methyl-4-[(3-(4-(((N',N'-dimethylaminocarbonyl)-N-methylamino)methyl)benzylthio)-5-fluorophenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 25,except substituting4-[(3-(4-((N',N'-dimethylaminocarbonyl)aminomethyl)benzylthio)-5-fluorophenyl)oxomethyl]-tetrahydropyran,prepared as in Example 31, for4-[(3-(4-((N',N'-dimethylaminocarbonyl)aminomethyl)benzyloxy)-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 34

Preparation of E- andZ-O-Methyl-4-[(3-(4-(((N',N'-dimethylaminocarbonyl)-N-methylamino)methyl)benzylthio)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 25,except substituting4-[(3-(4-((N',N'-dimethylaminocarbonyl)aminomethyl)benzylthio)phenyl)-oxomethyl]tetrahydropyran,prepared as in Example 32, for4-[(3-(4-((N',N'-dimethylaminocarbonyl)aminomethyl)benzyloxy)-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 35

Preparation of E andZ-O-Methyl-4-[(3-(4-(N-acetyl)aminomethyl)benzylthio)-5-fluorophenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 24,except substituting4-[(3-thioxy-5-fluorophenyl)oxomethyl]tetrahydropyran, prepared as inExample 17, for 4-[(3-hydroxy-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 36

Preparation of E andZ-O-Methyl-4-[(3-(4-(N-acetyl)aminomethyl)benzylthio)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 24,except substituting 4-[(3-thiophenyl)oxomethyl[tetrahydropyran, preparedas in Example 13, step 1, for4-[(3-hydroxy-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 37

Preparation of E andZ-O-Methyl-4-[(3-(4-(N-acetyl-N-methyl)aminomethyl)benzylthio)-5-fluorophenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 26,except substituting4-[(3-(4-(N-acetyl)aminomethyl)benzylthio)-5-fluorophenyl)oximinomethyl]tetrahydropyran,prepared as in Example 35, for4-[(3-(4-(N-acetyl)aminomethyl)benzyloxy)-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 38

Preparation of E andZ-O-Methyl-4-[(3-(4-(N-acetyl-N-methyl)aminomethyl)benzylthio)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 26,except substituting4-[(3-(4-(N-acetyl)aminomethyl)benzylthio)phenyl)oximinomethyl]-tetrahydropyran,prepared as in Example 36, for4-[(3-(4-(N-acetyl)aminomethyl)benzyloxy)-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 39

Preparation of E andZ-O-Methyl-4-[(3-(4-(imidazolidin-2-on-1-ylmethyl)benzyloxy)-5-fluorophenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 23,except substituting 2-imidazolidinone for 1,1-dimethylurea.

EXAMPLE 40

Preparation of E andZ-O-Methyl-4-[(3-(4-(imidazolidin-2-on-1-ylmethyl)benzyloxy)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 39,except substituting 4-[(3-hydroxyphenyl)oxomethyl]tetrahydropyran,prepared as in Example 3, step 3, for4-[(3-hydroxy-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 41

Preparation of E andZ-O-Methyl-4-[(3-(4-(imidazolidin-2-on-1-ylmethyl)benzylthio-5-fluorophenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 39,except substituting4-[(3-thioxy-5-fluorophenyl)oxomethyl]tetrahydropyran, prepared as inExample 17, for 4-[(3-hydroxy-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 42

Preparation of E andZ-O-Methyl-4-[(3-(4-imidazolidin-2-on-1-ylmethyl)benzylthio)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 39,except substituting 4-[(3-thioxyphenyl)oxomethyl]tetrahydropyran,prepared as in Example 13, step 1, for4-[(3-hydroxy-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 43

Preparation of E- andZ-O-Methyl-4-[(3-(3-(N',N'-dimethylaminocarbonyl-N-methylamino)-benzyloxy)-5-fluoro-phenyl)oximinomethyl]tetrahydropyran.

Step 1. Preparation of 3-(O-t-butyldimethylsilyloxymethyl)aniline.

To a solution of 3-aminobenzyl alcohol (2.00 g, 16.2 mmol) andtert-butyldimethylsilyl chloride (2.90 g, 19.4 mmol) in CH₂ Cl₂ (32.5mL) was added triethylamine (7.45 mL, 53.5 mmol). The reaction mixturewas stirred for 18 hours at ambient temperature and was then partitionedbetween ethyl acetate and H₂ O. The organic phase was washed twice withH₂ O, twice with brine, dried over MgSO₄, filtered, and concentrated invacuo. 3-(O-t-butyldimethylsilyloxymethyl)aniline (2.18 g, 57%) wasobtained as a yellow oil by chromatography on silica gel (30% ethylacetate/hexane). ¹ H NMR (300 MHz, CDCl₃) δ7.10 (1H, t, J=7.5 Hz),6.67-6.72 (2H, m), 6.56 (1H, br d, J=7.5 Hz), 4.66 (2H, s), 3.63 (2H, brs), 0.94 (9H, s), 0.09 (6H, s). MS m/e 238 (M+H)⁺, 255 (M+NH₄)³⁰ .

Step 2. Preparation ofO-t-butyldimethylsilyl-3-[(N'-methylaminocarbonyl)amino]benzyl alcohol.

To a solution under N₂ of 3-(O-t-butyldimethylsilyloxymethyl)aniline(900 mg, 3.79 mmol) in toluene (7.6 mL) was added methylisocyanate (0.45mL, 7.58 mmol). The reaction mixture was stirred at 100° C. for 1.5hours and was then cooled to ambient temperature and partitioned betweenethyl acetate and H₂ O. The organic phase was washed once with H₂ O,twice with brine, dried over MgSO₄, filtered, and concentrated in vacuo.The oily residue crystallized on standing. The crystalline solid waswashed twice with hexane to provideO-t-butyldimethylsilyl-3-[(N'-methylaminocarbonyl)amino]benzyl alcohol(641 mg, 57%). mp 110°-113° C. ¹ H NMR (300 MHz, CDCl₃) δ7.23-7.28 (2H,m), 7.17 (1H, d, J=7.5 Hz), 7.03 (1H, d, J=7.5 Hz), 6.68 (1H, br s), 5.0(1H, br q, J=4 Hz), 4.69 (2H, s), 2.80 (3H, d, J=5 Hz), 0.93 (9H, s),0.09 (6H, s). MS m/e 295(M+H)⁺, 312 (M+NH₄)⁺.

Step 3. Preparation ofO-t-butyldimethylsilyl-3-[(N'-N'-dimethylaminocarbonyl)-N-methylamino]benzylalcohol.

The desired compound was prepared according to the method of Example 5,step 2, except substitutingO-t-butyldimethylsilyl-3-[(N'-methylaminocarbonyl)amino]benzyl alcohol,prepared as in step 2, for methyl4-(N-methylaminocarbonyl)aminobenzoate. ¹ H NMR (300 MHz, CDCl₃) δ7.27(1H, t, J=7.5 Hz), 7.00-7.06 (2H, m), 6.92 (1H, br d, J=7.5 Hz), 4.71(2H, s), 3.21 (3H, s), 2.68 (6H, s),0.93 (9H, s), 0.09 (6H, s); MS m/e323 (M+H)⁺ ; 340 (M+NH₄)⁺.

Step 4. Preparation of3-[(N'-N'-dimethylaminocarbonyl)-N-methylamino]benzyl bromide.

To a solution ofO-t-butyldimethylsilyl-3-[(N'-N'-methylaminocarbonyl)-N-methylamino]benzylalcohol (371 mg, 1.15 mmol) in CH₂ Cl₂ (5.7 mL) was added a solution ofdibromotriphenylphosphorane (1.45 g, 3.45 mmol) in CH₂ Cl₂ (5.7 mL). Thereaction mixture was stirred for stirred for 1.5 hours at ambienttemperature and was then partitioned between ethyl acetate and H₂ O. Theorganic phase was washed twice with H₂ O, twice with brine, dried overMgSO₄, filtered, and concentrated in vacuo. Pure3-[(N'-N'-methylaminocarbonyl)-N-methylamino]benzyl bromide (282 mg,90%) was obtained by chromatography on silica gel. ¹ H NMR (300 MHz,CDCl₃) δ7.29 (1H, t, J=7.5 Hz), 7.06-7.12 (2H, m), 6.98 (1H, br d, J=7.5Hz), 4.46 (2H, s), 3.21 (3H, s), 2.72 (6H, s),0.93 (9H, s), 0.09 (6H,s). MS m/e 271/273 (M+H)⁺, 288/290 (M+NH₄)⁺.

Step 5. Preparation of E- andZ-O-Methyl-4-[(3-(3-(N',N'-dimethylaminocarbonyl-N-methylamino)benzyloxy)-5-fluoro-phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 5,step 5, except substituting3-[(N'-N'-dimethylaminocarbonyl)-N-methylamino]benzyl bromide, preparedas in step 4, for 4-[(N'-N'-dimethylaminocarbonyl)-N-methylamino]benzylchloride.

EXAMPLE 44

Preparation of E- andZ-O-Methyl-4-[(3-(3-N',N'-dimethylaminocarbonyl-N-methylamino)-benzyloxy)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 43,except substituting 4-[(3-hydroxyphenyl)oxomethyl]tetrahydropyran,prepared as in Example 3, step 3, for4-[(3-hydroxy5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 45

Preparation of E- andZ-O-Methyl-4-[(3-(3-(N',N'-dimethylaminocarbonyl-N-methylamino)-benzylthio)-5-fluorophenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 43,except substituting4-[(3-thioxy-5-fluorophenyl)oxomethyl]tetrahydropyran, prepared as inExample 17, for 4-[(3-hydroxy-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 46

Preparation of E- andZ-O-Methyl-4-[(3-(3-(N',N'-dimethylaminocarbonyl-N-methylamino)-benzylthio)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 45,except substituting 4-[(3-thioxyphenyl)oxomethyl]tetrahydropyran,prepared as in Example 13, step 1, for4-[(3-thioxy-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 47

Preparation of E- andZ-O-Methyl-4-[(3-(3-(N-acetyl-N-methylamino)benzyloxy)-5-fluoro-phenyl)oximinomethyl]tetrahydropyran.

Step 1. Preparation of O-t-butyldimethylsilyl-3-[(N-acetyl))amino]benzylalcohol.

The desired material is prepared according to the method of Example 1,step 1, except substituting 3-(O-t-butyldimethylsilyloxymethyl)aniline,prepared as in Example 45, step 1, for N-methyl-4-aminobenzoic acid.

Step 2. Preparation ofO-t-butyldimethylsilyl-3-[(N-acetyl-N-methyl))amino]benzyl alcohol.

The desired material is prepared according to the method of Example 5,step 2, except substitutingO-t-butyldimethylsilyl-3-[(N-acetyl))amino]benzyl alcohol, prepared asin step 1, for methyl 4-(N-methylaminocarbonyl)aminobenzoate.

Step 3. Preparation of E- andZ-O-Methyl-4-[(3-(3-(N-acetyl-N-methylamino)benzyloxy)-5-fluoro-phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 43,steps 4-5, except substitutingO-t-butyldimethylsilyl-3-[(N-acetyl-N-methyl))amino]benzyl alcohol,prepared as in step 2, forO-t-butyldimethylsilyl-3-[(N'-N'-methylaminocarbonyl)-N-methylamino]benzylalcohol.

EXAMPLE 48

Preparation of E- andZ-O-Methyl-4-[(3-(3-(N-acetyl-N-methylamino)benzyloxy)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 47,except substituting 4-[(3-hydroxyphenyl)oxomethyl]tetrahydropyran,prepared as in Example 3, step 3, for4-[(3-hydroxy-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 49

Preparation of E- andZ-O-Methyl-4-[(3-(3-(N-acetyl-N-methylamino)benzylthio)-5-fluoro-phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 47,except substituting4-[(3-thioxy-5-fluorophenyl)oxomethyl]tetrahydropyran, prepared as inExample 17, for 4-[(3-hydroxy-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 50

Preparation of E- andZ-O-Methyl-4-[(3-(3-(N-acetyl-N-methylamino)benzylthio)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 49,except substituting 4-[(3-thioxyphenyl)oxomethyl]tetrahydropyran,prepared as in Example 13, step 1, for4-[(3-thioxy-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 51

Preparation of E- andZ-O-Methyl-4-[(3-(3-(N'N'-dimethylaminocarbonyl-N-methylamino)-benzylamino)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 43except substituting 4-[(3-aminophenyl)oxomethyl]tetrahydropyran,prepared as in Example 9, step 3, for4-[(3-hydroxy-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 52

Preparation of E- andZ-O-Methyl-4-[(3-(3-(N-acetyl-N-methylamino)benzylamino)phenyl)oximinomethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 47,except substituting 4-[(3-aminophenyl)oxomethyl]tetrahydropyran,prepared as in Example 9, step 3, for4-[(3-hydroxy-5-fluorophenyl)oxomethyl]tetrahydropyran.

EXAMPLE 53

Preparation of4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)-5-fluoro-phenyl)methoxymethyl]tetrahydropyran.

Step 1. Preparation of4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)-5-fluoro-phenyl)hydroxymethyl]tetrahydropyran.

The desired material is prepared by reduction of4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)-5-fluoro-phenyl)oxomethyl]tetrahydropyran,prepared as in Example 1, with NaBH₄.

Step 2, Preparation of4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)-5-fluoro-phenyl)methoxymethyl]tetrahydropyran.

The desired compound is prepared according to the method of Example 5,step 2, except substituting4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)-5-fluoro-phenyl)hydroxymethyl]tetrahydropyran,prepared as in step 1, for methyl4-(N-methylaminocarbonyl)aminobenzoate.

The compounds represented in Table 2 are prepared according to themethod of Example 55, except substituting the corresponding ketone for4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)-5-fluoro-phenyl)oxomethyl]tetrahydropyran.

                                      TABLE 2                                     __________________________________________________________________________    Example                                                                            Product                                                                  __________________________________________________________________________    54                                                                                  ##STR20##                                                               55                                                                                  ##STR21##                                                               56                                                                                  ##STR22##                                                               57                                                                                  ##STR23##                                                               58                                                                                  ##STR24##                                                               59                                                                                  ##STR25##                                                               60                                                                                  ##STR26##                                                               61                                                                                  ##STR27##                                                               62                                                                                  ##STR28##                                                               63                                                                                  ##STR29##                                                               64                                                                                  ##STR30##                                                               65                                                                                  ##STR31##                                                               66                                                                                  ##STR32##                                                               67                                                                                  ##STR33##                                                               68                                                                                  ##STR34##                                                               69                                                                                  ##STR35##                                                               70                                                                                  ##STR36##                                                               71                                                                                  ##STR37##                                                               72                                                                                  ##STR38##                                                               73                                                                                  ##STR39##                                                               74                                                                                  ##STR40##                                                               75                                                                                  ##STR41##                                                               76                                                                                  ##STR42##                                                               77                                                                                  ##STR43##                                                               78                                                                                  ##STR44##                                                               79                                                                                  ##STR45##                                                               80                                                                                  ##STR46##                                                               81                                                                                  ##STR47##                                                               82                                                                                  ##STR48##                                                               83                                                                                  ##STR49##                                                               84                                                                                  ##STR50##                                                               85                                                                                  ##STR51##                                                               86                                                                                  ##STR52##                                                               87                                                                                  ##STR53##                                                               __________________________________________________________________________

The compounds represented in Table 3 are prepared by treatment ofarylalkylamine 12 with trimethylsilylisocyanate, with R⁷ NCO, or withRLi and R⁶ R⁷ NCOCl as described in Scheme 2.

                  TABLE 3                                                         ______________________________________                                        Novel N-alkylurea inhibitors of 5-lipoxygenase                                 ##STR54##                                                                     ##STR55##                                                                    Example      R.sup.5   R.sup.6  R.sup.7                                       ______________________________________                                        88           Me        H        H                                             89           Me        H        Me                                            90           Me        H        Et                                            91           Me        H        Pr                                            92           Me        H        Bu                                            93           Me        Et       Me                                            94           Me        Pr       Me                                            95           Me        Bu       Me                                            96           Me        Et       Et                                            97           Me        Pr       Pr                                            98           Me        Bu       Bu                                            99           Me        Ph       H                                             100          Me        Ph       Me                                            101          Me                                                                                       ##STR56##                                             102          Me                                                                                       ##STR57##                                             103          Me                                                                                       ##STR58##                                             104          Me                                                                                       ##STR59##                                             105          Me                                                                                       ##STR60##                                             106          Et        H        Me                                            107          Et        Me       Me                                            108          Pr        H        Me                                            109          Pr        Me       Me                                            110          Bu        H        Me                                            111          Bu        Me       Me                                            ______________________________________                                    

The compounds represented in Table 4 are prepared by reaction ofisocyanate 16 with HNR⁶ R⁷.

                  TABLE 4                                                         ______________________________________                                        Novel haloalkyl-,                                                             hydroxyalkyl-, aminoalkyl-, (alkoxycarbonyl)alkyl-,                           carboxyalkyl-, and (aminoalkylcarbonyl)alkylurea                              derivatives of 5-Lipoxygenase.                                                 ##STR61##                                                                    Example   R.sup.5                                                                              R.sup.7            R.sup.6                                   ______________________________________                                        112       Me                                                                                    ##STR62##         H                                         113       Me                                                                                    ##STR63##         Me                                        114       Me                                                                                    ##STR64##         H                                         115       Me                                                                                    ##STR65##         Me                                        116       Me                                                                                    ##STR66##         H                                         117       Me                                                                                    ##STR67##         Me                                        118       Me                                                                                    ##STR68##         H                                         119       Me                                                                                    ##STR69##         Me                                        120       Me                                                                                    ##STR70##         H                                         121       Me                                                                                    ##STR71##         Me                                        122       Me                                                                                    ##STR72##         H                                         123       Me                                                                                    ##STR73##         Me                                        ______________________________________                                    

The compounds represented in Table 5 are prepared as described in Scheme6.

                  TABLE 5                                                         ______________________________________                                        Novel N-acyl inhibitors of 5-Lipoxygenase                                      ##STR74##                                                                    Example         R.sup.8                                                       ______________________________________                                        124                                                                                            ##STR75##                                                    125                                                                                            ##STR76##                                                    126                                                                                            ##STR77##                                                    127                                                                                            ##STR78##                                                    128                                                                                            ##STR79##                                                    129                                                                                            ##STR80##                                                    130                                                                                            ##STR81##                                                    ______________________________________                                    

We claim:
 1. A compound having the structure ##STR82## or apharmaceutically acceptable salt thereof wherein R⁵ and R⁶ areindependently selected from hydrogen and alkyl of one to four carbonatoms, provided that when L¹ is a valence bond, R⁵ is alkyl of one tofour carbon atoms, orR⁵ and R⁶, together with the nitrogen atoms towhich they are attached, define a radical of the formulae ##STR83## Q isoxygen or sulfur, R⁷ is selected from the group consisting of hydrogen,and alkyl of one to four carbon atoms; L¹ is a valence bond or isselected from alkylene of one to three carbon atoms, propenylene, andpropynylene; R¹, R², R³, and R⁴ are independently selected from thegroup consisting of hydrogen, alkyl of one to four carbon atoms, alkoxyof one to four carbon atoms, haloalkyl, and halogen; L² is a valencebond or is selected from alkylene of one to three carbon atoms,propenylene, and propynylene; Y is oxygen, and R¹¹ is hydrogen or alkylof one to four carbon atoms.
 2. A compound as defined in claim 1 havingthe structure ##STR84## or a pharmaceutically acceptable salt thereofwherein R⁴, R⁵, R⁶, R⁷, and R¹¹ are defined therein.
 3. A compound orpharmaceutically acceptable salt thereof selected from the groupconsisting of:E andZ-O-Methyl-4-[(3-(4-(N-acetyl-N-methylamino)benzyloxy)-5-fluoro-phenyl)oximinomethyl]tetrahydropyran,E andZ-O-Methyl-4-[(3-(4-(N',N'-dimethylaminocarbonyl-N-methylamino)-benzyloxy)-5-fluorophenyl)oximinomethyl]tetrahydropyran,and E andZ-O-Methyl-4-[(3-(4-(N',N'-dimethylaminocarbonyl-N-methylamino)phenylthio)phenyl)oximinomethyl]tetrahydropyran.4. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound as defined in claim 1 in combination with apharmaceutically acceptable carrier.
 5. A method of inhibiting5-lipoxygenase enzyme activity in a mammal in need of such treatmentcomprising administering an effective amount of a compound as defined inclaim 1.